This week there have been a flurry of breathless headlines suggesting a medical breakthrough is on the way. “In the first instance, two people donate blood cells grown in the lab.” Such a topic is particularly appealing as the holidays approach and the call for blood donations increases, as supplies always seem to dwindle. Does a title like this mean someone is making completely artificial blood?

As always with this sort of thing, the answer is a mixed bag. Yes, a team in the UK has given blood to two patients with minimally lab-grown red blood cells, and this is the first time that this particular procedure has been done. But while the subject was technically correct, the amount taken was too small, so the day when lab-made whole blood can replace donated blood isn’t quite here yet. But the details of what was done and why it was attempted is the most interesting part here, and it’s worth a deeper dive because it could point to a future where fully synthetic blood could become a reality.

Growing red

To understand what’s going on in this experiment, called “Retrieval and Resuscitation of Red Cells of Stem Cell Origin,” or Return to where it was, we must look at the process of blood formation in some detail. The journey from one cell type to whole blood filled with red blood cells, white blood cells, platelets, and a myriad of other specialized cells and factors is called hematopoiesis. It’s an extremely complex and tightly controlled process, but it all starts with the simplest and in some ways the most important cells in the body: stem cells, which are undifferentiated cells that can make unlimited copies of themselves.

Many branches, but one origin. A simplified view of hematopoiesis. Source: Cisco OnlineCC BY-SA 4.0

The stem cell at the root of hematopoiesis is called a hematopoiesis. In adults, hematopoiesis is found mainly in the bone marrow, especially in the sternum, vertebrae, ribs, and pelvis. In response to the presence or absence of certain growth factors, hematopoblasts undergo a series of divisions that lead to the formation of specialized cells with specialized functions. Some hemocytoblasts begin to go down the branch that leads to different types of cells in our immune system, such as leukocytes, or white blood cells, while others begin the process of differentiating into cells designed to transport oxygen and carbon dioxide. Red blood cells (RBCs), also called erythrocytes.

In the process of differentiation or erythropoiesis, stem cells undergo significant changes in size and shape. The developing red blood cells shrink and begin to take on their characteristic biconcave disc shape. Genes that code for heme proteins begin to be expressed, and the developing erythrocytes begin to turn red as the oxygen-carrying protein hemoglobin accumulates in the cytoplasm. Finally, the nucleus that was in the red blood cell is removed from the erythrocyte, which has decreased during the entire process of differentiation, leaving a small hemoglobin bag and not much.

The immature red blood cells at this stage are called reticulocytes. At this time, they migrate from the bone and move to the circulation, and then grow into erythrocytes in two days. Reticulocytes make up about 1% of RBCs at any given time in a healthy patient, with the remaining 99% being mixed populations up to about four months of age. When they get that old, RBCs are too damaged to do their job, so they are removed from circulation and recycled by the spleen.

Baby blood cells

In a healthy adult, erythropoiesis is a highly productive process; Although it takes three weeks to go from stem cell to reticulocyte, the bone marrow puts about 200 billion new RBCs into circulation every day. This ability to rapidly build up a pool of RBCs is key to blood donation; Normally, blood donors make a full recovery if they give half a liter of whole blood within 20 days. Because of this rapid recycling, blood donation has become an absolutely vital life-saving tool used to treat a wide range of diseases and disorders.

Photomicrograph of erythrocytes. Source: By Dr. Noguchi, Rogers, and Schechter NIDDK National Institutes of Health. Public domain.

But as life-saving as a whole blood transfusion, complications can occur. Red blood cells contain protein substances on their surface – the well-known “ABO” groups – when carefully typed and combined, they can eventually increase the immune response in the recipient. This is particularly common in those with anemia such as sickle cell anemia or thalassemia, or in frequent blood recipients with anemia such as hemophilia.

One way to primarily address the issue of developing a “blood allergy” is to increase the time between transfusions, and that’s what the RESTORE trial addresses. Instead of transfusing whole blood containing long-lived RBCs, they want to be able to transfuse patients where every RBC is the same age and fresh. In this way, at least theoretically, the transfused RBCs survive their full 120-day life, rather than being continuously retired from the time of transfusion.

The first step in testing how useful laboratory blood is in treating diseases is to draw a small amount of blood. Although there are no published papers from the RESTORE trial yet, Erythropoiesis in vitro It has been a pretty standard laboratory procedure for decades. The methods vary, but from the description given by the RESTORE group, it is likely that they are isolating and multiplying the small hematopoietic stem cells that are circulating in the blood along with the mature cells. These cells have antibodies on them that mature red blood cells lack, and that fact can be used to distinguish them from the rest of the cells. A small number of stem cells can be grown in a suitable growth area.

The culture can be treated with erythropoietin to convert the stem cells into RBCs. Erythropoietin or EPO is produced when the body senses low blood oxygen. To increase the oxygen carrying capacity of the blood, the body responds by stimulating the differentiation of stem cells into RBCs. EPO gained popularity as a stimulant drug in the 1990s when it was used by athletes, particularly cyclists, to increase blood oxygen-carrying capacity.

For the RESTORE study, whole blood is obtained from healthy donors, stem cells are purified from whole blood and RBCs are cultured. An aliquot of whole blood was used as a control. Both blood components are labeled with a small amount of radioactive tracer. On the donor side, healthy volunteers give small amounts – a few milliliters – of cultured blood. They will be followed over the next four months, and a sample of their blood will be analyzed to see how many cultured RBCs remain. After all cultured blood is filtered, the experiment is repeated with donated blood.

If all goes well, the RESTORE team will transfer a total of ten volunteers. Cultured RBCs are expected to stay in the blood longer than whole blood transfusions; If so, this could open the door to improved treatments for patients who need frequent blood transfusions. There’s a lot of ground to cover before then, of course, at least currently developing a method to produce enough RBCs for one person.

The future of artificial blood

But could the same process one day result in fully lab-grown whole blood? Maybe, but whole blood is more complex than RBCs, and learning to grow it in large quantities is more difficult. This is the first possible stem cell: the hematoblast. Because every cell in whole blood descends from that cell type, whole blood must be able to grow in vitro. This does not mean that the process will be entirely artificial. Those stem cells have to come from somewhere, and the most obvious source would be human donors. That raises the question of why bother with in vitro standards; If you have to get a donation, just take whole blood and put it on him, right?

While this is true, converting donated stem cells into artificial whole blood has significant benefits. The main advantage is that stem cells are immortal, so one donation can create an unlimited amount of whole blood. This can be a huge advantage anywhere the pool of blood donors is limited, but there may still be a need for blood in an emergency – think space travel. And although generating whole blood from stem cell culture is almost impossible, being able to maximize erythrocyte production and mix it with donated plasma can be very beneficial – thankfully. plasmapheresisPlasma can be donated more often than whole blood.

The day when whole human blood donation will no longer be necessary will probably never come, and if it ever does, it is far away. But it’s exciting news that the RESTORE trial was able to grow even the few milliliters of blood needed to do their first experiment. This trial will not only bring tangible benefits to patients currently in need, but will also open the door to unlimited whole blood on demand.

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